Iodine loaded nanoparticles with commercial applicability increase survival in mice cancer models with low degree of side effects

Abstract

Background: The recorded use of iodine in medicine, dates to 5000 BC. Molecular iodine (I₂ ) has been claimed to exert an antineoplastic effect that triggers apoptotic and re-differentiation mechanisms in different types of cancer cells in animal studies. Hitherto, all experiments published have been carried out with I₂ diluted in water preparations resulting in the administration of ionized iodide, either alone or in combination with low levels of I₂ . To maximize the levels of I₂ by avoiding water solutions we have managed to develop a colloidal nano particle (NP) loaded with I₂ with a Z-average of 7-23 nm with remarkable stability, preferable osmolality and commercial applicability.

Aims: Here we report the results from formulation and pre-clinical studies with the rationale: a) to find a tolerable dose of the I₂ NP system delivered intravenously or per-orally, and b) to determine if the tolerable doses are efficacious in murine models of cancer.

Methods and results: A novel drug delivery system with I₂ NP was formulated and murine cancer models with CT26, MDA-MB-231 and LL/2 cells were used to analyse the efficacy. Despite the formulation challenges we were successful in constructing stable NPs loaded with I₂ which have convincing commercial applicability. We conclude that administration of the NP I₂ drug delivery system: 1. Blunted tumour growth in a xenograft breast cancer model; 2. Had a significant effect on survival in the orthotopic, syngeneic lung metastasis model; 3. Showed reduced tumour burden in post-mortem evaluation and; 4. Was associated with low degree of side effects.

Conclusions: Taken all together, our findings indicate that the NP I₂ drug delivery system may serve as a novel effective cancer treatment with low degree of side effects. This is something which needs further exploration including confirmation in future clinical trials.

Keywords: cytotoxic; drug delivery; molecular iodine; nanoparticles; side effects.

FIGURE 1

CIP3 – Minor colour difference after 29 weeks between storage at 5°C (right) and 25°C (left).

FIGURE 2

Summary of the animal experiments performed.

FIGURE 3

Plasma concentrations of colloidal iodine following intravenous (27 mg/kg) or per‐oral (74.78) administration of CIP1, at an acidic pH.

FIGURE 4

Absolute (A) and relative (B) growth of CT26 tumours following repeated administration of vehicle or CIP1, via intravenous or per‐oral delivery. Relative growth is calculated as percent of volume on Day 0. Data is presented as mean ± SEM, n = 9–17.

FIGURE 5

Absolute (A) and relative (B) tumour growth of MDA‐MB‐231 tumours and relative body weight (C) following repeated administration of vehicle or CIP1, via intravenous or per‐oral delivery or cisplatin. Relative growth is calculated as percent of volume/body weight on Day 0. Data is presented as mean ± SEM, n = 8. An asterisk indicates a p‐value <.05.

FIGURE 6

Survival (A) and number of small (B) and large (C) lung tumours, as evaluated post‐mortem, following inoculation with LL/2 cells and repeated administration of vehicle or CIP1, via intravenous or per‐oral delivery. A tumour with a diameter of <3 mm was considered small; a tumour with a diameter of >3 mm was considered large. In bar graphs, data is presented as mean ± SEM, n = 8 for survival graph; n = 4–8 for tumour burden. An asterisk indicates a p‐value <.05.

FIGURE 7

Survival (A) and number of small (B) and large (C) lung tumours, as evaluated post‐mortem, following inoculation with LL/2 cells and repeated administration of vehicle, CIP1 or CIP3, via intravenous or per‐oral delivery, or cisplatin. A tumour with a diameter of <3 mm was considered small; a tumour with a diameter of >3 mm was considered large. In bar graphs, data is presented as mean ± SEM, n = 8 for survival graph; n = 4–8 for tumour burden. An asterisk indicates a p‐value <.05.